Uric acid is an independent risk factor for carotid atherosclerosis in a Japanese elderly population without metabolic syndrome

Subjects for this investigation were recruited from among consecutive elderly patients aged ≥65 years visited the medical department of Seiyo Municipal Nomura Hospital. Participants with severe cardio-renal or nutritional disorders that would affect BP, lipid and glucose metabolism were excluded. Thus, 1,579 patients were enrolled in the study. All procedures were approved by the Ethics Committee of Seiyo Municipal Nomura Hospital, and written informed consent was obtained from each subject.

Information on demographic characteristics and risk factors were collected using the clinical files in all cases. Body mass index (BMI) was calculated by dividing weight (in kilograms) by the square of the height (in meters). We measured BP in the right upper arm of patients in a sedentary posture using a standard sphygmomanometer or an automatic oscillometric BP recorder. Smoking status was defined as the number of cigarette packs per day multiplied by the number of years smoked (pack·year) irrespective of the differentiation of current and past smoking status: never, light (< 20 pack·year), heavy (≥20 pack·year). Alcohol consumption was classified into non-drinker and drinker (available data, n = 1,145). Histories of antihypertensive, antilipidemic, and antidiabetic medication use were also evaluated. Moreover, ischemic stroke and ischemic heart disease were defined as CVD. Total cholesterol (T-C), triglyceride (TG), HDL cholesterol (HDL-C), FPG, and UA were measured under a fasting condition. Low-density lipoprotein cholesterol (LDL-C) level was calculated by the Friedewald formula [16], and patients with TG levels ≥400 mg/dl were excluded. The mean UA was significantly lower in women [5.1 ± 2.0 {mean ± standard deviation (SD)} mg/dl] than in men (5.7 ± 2.0 mg/dl; p < 0.001). Therefore, sex-specific quartiles of UA were used. The mean (range) UA values of 3.5 (0.8 to 4.3), 5.0 (4.4 to 5.5), 6.1 (5.6 to 6.8), and 8.4 (6.9 to 16.1) mg/dl were used for men, and 3.1 (0.5 to 3.8), 4.3 (3.9 to 4.7), 5.3 (4.8 to 6.0), and 7.7 (6.1 to 15.4) were used for women (Table 1).

An ultrasonograph (Hitachi EUB-565, Aloka SSD-2000, or Prosound-α6) equipped with a 7.5 MHz linear type B-mode probe was used by a specialist in ultrasonography to evaluate sclerotic lesions of the common carotid arteries on a day close to the day of blood biochemistry analysis (within 2 days). Patients were asked to assume a supine position, and the bilateral carotid arteries were observed obliquely from the anterior and posterior directions. We measured the thickness of the intima-media complex (IMT) on the far wall of the bilateral common carotid artery about 10 mm proximal to the bifurcation of the carotid artery (as the image at that site is more clearly depicted than that at the near wall) [17, 18] as well as the wall thickness near the 10 mm point on a B-mode monitor. We then used the mean value for analysis. Carotid plaques were considered as localized thickening and the echo luminance included those equal to high echogenic structures encroaching into the vessel lumen through common carotid artery to carotid bifurcation [17]. Carotid atherosclerosis was defined as IMT ≥1.0 mm or plaque lesion [17‐19].

We applied condition-specific cutoff points for MetS based on the modified criteria of the National Cholesterol Education Program's Adult Treatment Panel (NCEP-ATP) III report [2]. MetS was defined as subjects with at least three or more of the following five conditions: 1) obesity: BMI ≥25.0 kg/m² according to the guidelines of the Japanese Society for the Study of Obesity (waist circumference was not available in this study) [20, 21]; 2) raised BP with a systolic BP (SBP) ≥130 mmHg and/or diastolic BP (DBP) ≥85 mmHg, and/or current treatment for hypertension; 3) hypertriglyceridemia with a TG level ≥150 mg/dL; 4) low HDL cholesterolemia with a HDL-C level < 40 mg/dL in men and < 50 mg/dL in women and/or current treatment for dyslipidemia; and 5) impaired fasting glucose with a FPG level ≥100 mg/dL and/or current treatment for diabetes.

All values are expressed as the mean ± standard deviation (SD), unless otherwise specified, and in the cases of parameters with non-normal distributions (TG, FPG), the data are shown as median (interquartile range) values. In all analyses, parameters with non-normal distributions were used after log-transformation. Statistical analysis was performed using PASW Statistics 17.0 (Statistical Package for Social Science Japan, Inc., Tokyo, Japan). The differences of means and prevalence among the groups were analyzed by ANOVA and χ² test, respectively, and A post hoc analysis was performed with Dunnett's test. A multivariate logistic regression analysis was employed to evaluate the contribution of confounding risk factors (e.g., age, BMI, smoking status, SBP, DBP, antihypertensive medication, LDL-C, HDL-C, TG, antilipidemic medication, FPG, antidiabetic medication, and history of CVD) for carotid atherosclerosis. A value of p < 0.05 was considered significant.

Table 1 shows the clinical characteristics of the 663 male and 916 female subjects. Ages of the enrolled subjects ranged with a mean of 79 ± 8 years (men, 78 ± 8 years; women, 79 ± 8 years; P < 0.001). In men, age, prevalence of antihypertensive medication, and TG showed a gradual increasing trend. In women, age, prevalence of antihypertensive medication, TG and prevalence of Ischemic heart disease showed a gradual increasing trend and HDL-C showed a gradual decrease. The prevalence of MetS also showed a gradual increasing according to the UA quartiles in both genders. There were no inter-group differences in prevalence of alcohol consumption, FPG, prevalence of antidiabetic and antilipidemic medication in both genders.

As shown in Table 2, carotid IMT was significantly increased according to the UA quartiles in both genders without MetS and in women with MetS, but was not necessarily increased in men with MetS. As shown in Figure 1, the prevalence of carotid atherosclerosis was significantly increased with increased UA quartile in both genders without MetS.

In Table 3, to examine possible associations between quartiles of UA and the incidence of carotid atherosclerosis after subdivision of the subjects according to MetS status, multivariate logistic regression analysis was performed adjusted for age, gender, BMI, smoking status, SBP, DBP, antihypertensive medication, LDL-C, HDL-C, TG, antilipidemic medication, FPG, antidiabetic medication, and history of CVD. In men, ORs (95% CI) were significantly increased in the third {1.75 (1.02-3.02)} and fourth quartiles {2.01 (1.12-3.60)} of UA compared with that in the first quartile, and in women the OR was significantly increased only in the fourth quartile {2.10 (1.30-3.39)}. Similarly, the ORs were significantly associated with increasing quartiles of UA in both genders without MetS, but not necessarily increased in those with MetS.

Next, to control potential confounding factors by age, BMI, history of CVD, and medication, the data were further stratified by their values (Table 4). In men, the ORs for carotid atherosclerosis were significant in subgroups of age ≥75 years, BMI ≥ 25 kg/m², no history of CVD, and absence of medication, and in women the ORs were significant in subgroups of age < 75 years, BMI ≥25 kg/m², regardless of history of CVD, presence of medication.